HT2C Receptors Activate Extracellular Signal Regulated Kinases

Because the 5-HT2C receptor regulates cell proliferation (Sect. 5.8.1), it is not surprising that the receptor could activate mitogenic kinases. The first evidence that 5-HT2C receptor is able to activate extracellular signal-regulated kinases xh (ERK1/2) when expressed in NIH 3 T3 cells was presented by Fitzgerald et al. (2000). Another group investigated the mechanism of coupling of 5-HT2C receptor to ERK1/2 using CHO cells that expressed the non-RNA-edited 5-HT2C-INI isoform of the human 5-HT2C receptor at levels comparable with those found in native neuronal preparations (Werry et al. 2005). The authors found that 5-HT2C receptor-stimulated ERK1/2 phosphorylation through a pathway that requires the involvement of the PTX-insensitive G proteins (most likely Ga12/13,), PLD, protein kinase C (PKC), and activation of the Raf/MEK/ERK module but that is independent of epidermal growth factor receptor (EGFR) tyrosine kinase and of nonreceptor tyrosine kinase Src, PLC, phosphoinositide 3-kinase (PI3-K), and receptor endocy-tosis (Werry et al. 2005). Later the same group expanded their studies of the mechanisms underlying 5-HT2C receptor-induced ERK1/2 activation using the non-RNA-edited 5-HT2C-INI isoform, fully edited 5-HT2C-VGV isoform, and partially edited but most abundant 5-HT2C-VSV isoform of the human 5-HT2C receptor expressed in CV1 kidney epithelial cells (Werry et al. 2008b). They found that 5-HT2C receptor-dependent activation of the ERK1/2 signaling cascade involves a variety of additional components, including activation of matrix metalloproteases, PKC, PI3-K, and transactivation of the EGFR, and that RNA editing of the 5-HT2C receptor has significant effects on its ability to signal to ERK1/2, changing both its temporal and pharmacological profiles, including the degree of dependence on specific effectors. Thus, while all three isoforms displayed a strong dependence on EGFR transactivation, the non-RNA-edited 5-HT2C-INI isoform did not utilize either PKC or PI3-K at early time points, the 5-HT2C-VSV isoform was connected with both

PKC and PI3-K, and 5-HT2C-VGV isoform recruited PKC to a significant degree (Werry et al. 2008b). 2C-VGV

These studies also support the notion that 5-HT2C receptor can generate different intracellular signals in a ligand-dependent manner (Berg et al. 1998) because agonist-directed trafficking of receptor stimuli was observed for some agonists when comparing ERK1/2 phosphorylation to IP3 accumulation and intracellular Ca2+ elevations (Werry et al. 2005) and because the contribution of different signaling molecules utilized by 5-HT2C receptor to stimulate ERK1/2 was dependent on the agonist used to stimulate the receptor (Werry et al. 2008b). However, a recent study by Knauer et al. has shown that a partially edited isoform of human 5-HT2C receptor (5-HT2C-isv), expressed in low densities in CHO cells, efficiently couples to ERK1/2 activation via PTX-insensitive G proteins and sequential PLC-dependent hydrolysis of PIP2, and Ca2+ mobilization, independent of both receptor and nonreceptor tyrosine kinases and PI3-K (Knauer et al. 2009). This study describes that 5-HT2C-ISV receptor-induced ERK1/2 activation resides mechanistically downstream of Ca2+ mobilization and PKC activation and does not support "agonist-directed trafficking" of receptor stimuli, and therefore is not consistent with the findings of Werry et al. (2005). One possible explanation of these discrepancies may be an effect of RNA editing, because Werry et al. studied the nonedited isoform of the human 5-HT2C receptor (Knauer et al. 2009).

On the other hand, Labasque et al. have demonstrated that 5-HT induced a rapid and sustained ERK1/2 activation in HEK-293 cells transiently transfected with 5-HT2C receptors, which was completely independent of Ga-protein subunits known to couple to the receptor (Labasque et al. 2008). That 5-HT2C receptor-mediated ERK1/2 signaling required Ca2+-dependent association of calmodulin (CaM) to the receptor C-terminus and subsequent recruitment of P-arrestin 2 by the receptor. Importantly, the Ca2+/CaM-dependent mechanism of ERK1/2 activation by 5-HT was demonstrated not only in transfected HEK 293 cells but also in choroid plexus epithelial cells, which express the highest 5-HT2C receptor density, and in cortical neurons transfected with a GFP-5-HT2C receptor construct (Labasque et al. 2008). A role for P-arrestin in the activation of ERK1/2 also has been demonstrated in the dendrites of cultured PFC pyramidal neurons, which endogenously express 5-HT2A and 5-HT2C receptors. Stimulation of 5-HT2A/C receptors triggered the activation of ERK1/2 by a mechanism that is independent of PLC but requires P-arrestin, Src activation, and clathrin/dynamin-mediated endocytosis of the receptor (Yuen et al. 2008). One group speculated that 5-HT2C receptor-dependent ERK1/2 activation might provide the molecular substrate for increased neurogenesis induced by chronic treatment with 5-HT2C agonists, a phenomenon that possibly is involved in their antidepressant effects (Millan 2005).

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